Volume 81, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


The mechanisms underlying the bleeding manifestations and coagulopathy associated with dengue remain unclear, in part because of the focus of much previous work on severe disease without an appropriate comparison group. We describe detailed clinical and laboratory profiles for a large group of children with dengue of all severities, and a group with similar non-dengue febrile illnesses, all followed prospectively from early presentation through to recovery. Among the dengue-infected patients but not the controls, thrombocytopenia, increased partial thromboplastin times and reduced fibrinogen concentrations were apparent from an early stage, and these abnormalities correlated strongly with the severity and timing of vascular leakage but not bleeding. There was little evidence of procoagulant activation. The findings do not support a primary diagnosis of disseminated intravascular coagulation to explain the intrinsic coagulopathy. An alternative biologically plausible hypothesis is discussed.


Article metrics loading...

Loading full text...

Full text loading...



  1. Monath TP, 1994. Dengue: the risk to developed and developing countries. Proc Natl Acad Sci USA 91: 2395–2400.
  2. Gubler DJ, 2002. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends Microbiol 10: 100–103.
  3. Mackenzie JS, Gubler DJ, Petersen LR, 2004. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 10: S98–S109.
  4. World Health Organization (WHO), 1997. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Second edition. Geneva: World Health Organization.
  5. Guzman MG, Kouri G, Bravo J, Valdes L, Vazquez S, Halstead SB, 2002. Effect of age on outcome of secondary dengue 2 infections. Int J Infect Dis 6: 118–124.
  6. Wichmann O, Hongsiriwon S, Bowonwatanuwong C, Chotivanich K, Sukthana Y, Pukrittayakamee S, 2004. Risk factors and clinical features associated with severe dengue infection in adults and children during the 2001 epidemic in Chonburi, Thailand. Trop Med Int Health 9: 1022–1029.
  7. Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, Tran VD, Nguyen TH, Nguyen VC, Stepniewska K, White NJ, Farrar JJ, 2005. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 353: 877–889.
  8. Srichaikul T, Nimmannitya S, 2000. Haematology in dengue and dengue haemorrhagic fever. Best Pract Res Clin Haematol 13: 261–276.
  9. Wills BA, Oragui EE, Stephens AC, Daramola OA, Dung NM, Loan HT, Chau NV, Chambers M, Stepniewska K, Farrar JJ, Levin M, 2002. Coagulation abnormalities in dengue hemorrhagic fever: serial investigations in 167 Vietnamese children with dengue shock syndrome. Clin Infect Dis 35: 277–285.
  10. Isarangkura PB, Pongpanich B, Pintadit P, Phanichyakarn P, Valyasevi A, 1987. Hemostatic derangement in dengue haemorrhagic fever. Southeast Asian J Trop Med Public Health 18: 331–339.
  11. Huang YH, Liu CC, Wang ST, Lei HY, Liu HL, Lin YS, Wu HL, Yeh TM, 2001. Activation of coagulation and fibrinolysis during dengue virus infection. J Med Virol 63: 247–251.
  12. Van Gorp EC, Setiati TE, Mairuhu AT, Suharti C, Cate Ht H, Dolmans WM, Van Der Meer JW, Hack CE, Brandjes DP, 2002. Impaired fibrinolysis in the pathogenesis of dengue hemorrhagic fever. J Med Virol 67: 549–554.
  13. Mairuhu AT, Mac Gillavry MR, Setiati TE, Soemantri A, ten Cate H, Brandjes DP, van Gorp EC, 2003. Is clinical outcome of dengue-virus infections influenced by coagulation and fibrinolysis? A critical review of the evidence. Lancet Infect Dis 3: 33–41.
  14. Carlos CC, Oishi K, Cinco MT, Mapua CA, Inoue S, Cruz DJ, Pancho MA, Tanig CZ, Matias RR, Morita K, Natividad FF, Igarashi A, Nagatake T, 2005. Comparison of clinical features and hematologic abnormalities between dengue fever and dengue hemorrhagic fever among children in the Philippines. Am J Trop Med Hyg 73: 435–440.
  15. Phuong CX, Nhan NT, Kneen R, Thuy PT, van Thien C, Nga NT, Thuy TT, Solomon T, Stepniewska K, Wills B, 2004. Clinical diagnosis and assessment of severity of confirmed dengue infections in Vietnamese children: is the world health organization classification system helpful? Am J Trop Med Hyg 70: 172–179.
  16. Balmaseda A, Hammond SN, Perez MA, Cuadra R, Solano S, Rocha J, Idiaquez W, Harris E, 2005. Short report: assessment of the World Health Organization scheme for classification of dengue severity in Nicaragua. Am J Trop Med Hyg 73: 1059–1062.
  17. Deen JL, Harris E, Wills B, Balmaseda A, Hammond SN, Rocha C, Dung NM, Hung NT, Hien TT, Farrar JJ, 2006. The WHO dengue classification and case definitions: time for a reassessment. Lancet 368: 170–173.
  18. Wali JP, Biswas A, Handa R, Aggarwal P, Wig N, Dwivedi SN, 1999. Dengue haemorrhagic fever in adults: a prospective study of 110 cases. Trop Doct 29: 27–30.
  19. Lanciotti RS, Calisher CH, Gubler DJ, Chang GJ, Vorndam AV, 1992. Rapid detection and typing of dengue viruses from clinical samples by using reverse transcriptase-polymerase chain reaction. J Clin Microbiol 30: 545–551.
  20. Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S, 1977. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg 26: 975–984.
  21. Krishnamurti C, Kalayanarooj S, Cutting MA, Peat RA, Rothwell SW, Reid TJ, Green S, Nisalak A, Endy TP, Vaughn DW, Nimmannitya S, Innis BL, 2001. Mechanisms of hemorrhage in dengue without circulatory collapse. Am J Trop Med Hyg 65: 840–847.
  22. Monroy V, Ruiz BH, 2000. Participation of the dengue virus in the fibrinolytic process. Virus Genes 21: 197–208.
  23. Markoff LJ, Innis BL, Houghten R, Henchal LS, 1991. Development of cross-reactive antibodies to plasminogen during the immune response to dengue virus infection. J Infect Dis 164: 294–301.
  24. Huang YH, Chang BI, Lei HY, Liu HS, Liu CC, Wu HL, Yeh TM, 1997. Antibodies against dengue virus E protein peptide bind to human plasminogen and inhibit plasmin activity. Clin Exp Immunol 110: 35–40.
  25. Michel CC, Curry FE, 1999. Microvascular permeability. Physiol Rev 79: 703–761.
  26. Vink H, Duling BR, 2000. Capillary endothelial surface layer selectively reduces plasma solute distribution volume. Am J Physiol Heart Circ Physiol 278: H285–H289.
  27. Wills BA, Oragui EE, Dung NM, Loan HT, Chau NV, Farrar JJ, Levin M, 2004. Size and charge characteristics of the protein leak in dengue shock syndrome. J Infect Dis 190: 810–818.
  28. Palmer RN, Rick ME, Rick PD, Zeller JA, Gralnick HR, 1984. Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder. N Engl J Med 310: 1696–1699.
  29. Bhamarapravati N, 1997. Pathology of infection. Gubler DJ, Kuno G, eds. Dengue and Dengue Hemorrhagic Fever. Wallingford: CAB International, 115–132.
  30. Kumar ND, Tomar V, Singh B, Kela K, 2000. Platelet transfusion practice during dengue fever epidemic. Indian J Pathol Microbiol 43: 55–60.
  31. Malavige GN, Velathanthiri VG, Wijewickrama ES, Fernando S, Jayaratne SD, Aaskov J, Seneviratne SL, 2006. Patterns of disease among adults hospitalized with dengue infections. QJM 99: 299–305.

Data & Media loading...

  • Received : 06 Jan 2008
  • Accepted : 15 Jul 2009

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error